CN106928298B - 环二核苷酸cGAMP衍生物的结构组成、制备方法及其在抗肿瘤中的应用 - Google Patents
环二核苷酸cGAMP衍生物的结构组成、制备方法及其在抗肿瘤中的应用 Download PDFInfo
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Abstract
本发明涉及生物医药技术领域，制备了系列环二核苷酸cGAMP的创新衍生物，该系列cGAMP的衍生物具有显著抗肿瘤作用，其在抗肿瘤和在制备抗肿瘤药物中具有重要潜在应用。
Description
技术领域
本发明涉及生物医药技术领域，具体为制备了系列环二核苷酸cGAMP的创新衍生物，该系列cGAMP的衍生物具有显著抗肿瘤作用，其在抗肿瘤和制备抗肿瘤药物中具有重要应用。
背景技术
恶性肿瘤是严重威胁人类健康的常见多发病，已成为人类死亡的一个重要原因。目前，肿瘤的主要治疗手段包括药物治疗、外科手术治疗和放射治疗。尽管以分子靶向药物为代表的新型抗肿瘤药物不断地涌现出来，在相当一段时期内，传统的细胞毒抗肿瘤药依然在肿瘤的药物治疗中占据主导地位。
传统的细胞毒抗肿瘤药主要通过影响肿瘤细胞的核酸和蛋白质结构与功能，直接抑制肿瘤细胞增殖或诱导肿瘤细胞凋亡。尽管人们在肿瘤的药物治疗方面做出很多努力，研究新的化疗药物，改进化疗方案，但是治疗效果仍不理想。传统的细胞毒抗肿瘤药对肿瘤细胞和正常细胞缺乏理想的选择作用，在杀伤恶性肿瘤细胞的同时，对人体的正常组织也有损害，从而导致严重的全身不良反应，其中比较常见的不良反应为骨髓抑制、消化道反应和脱发。所以很多患者无法坚持，甚至放弃化疗，临床上难以期望通过增加药物剂量来获得理想的效果。这些因素严重影响了化疗疗效。
最近有研究表明，环二核苷酸合成酶(cGAS)在结合DNA后的活化条件下催化cGAMP的合成，进一步通过STING介导IRF-3的活化，进而促进IFN-β的合成。外源性给予重组cGAS在DNA结合条件下促进环二核苷酸cGAMP的生成，发挥抗病毒、增强免疫的作用。也有专利报道，体外合成的环二核苷酸cGAMP具有抗肿瘤的应用。硫(硒)代磷酸环二核苷酸cGAMP具有比cGAMP更好的抗肿瘤活性。
本发明制备了系列环二核苷酸2’3’-cGAMP的创新衍生物，该系列衍生物比cGAMP具有更好的稳定性和与靶蛋白STING的亲和性，具有更好的抗肿瘤作用，其在抗肿瘤和制备抗肿瘤药物中具有重要的潜在应用。
发明内容
本发明的技术方案是提供了环二核苷酸cGAMP的系列衍生物的结构组成、制备方法、及其在抗肿瘤和制备抗肿瘤药物中的应用。
环二核苷酸cGAMP-XYZ衍生物的结构组成，主要指由2’3’-cGAMP进行修饰改造制备的cGAMP衍生物。分为如下几类：
(1)2’3’-cGAMP-X，cGAMP在腺嘌呤部分有取代基修饰的衍生物(2-R1/8-R2,R1/R2＝氨基、卤素、甲氧基等)
(2)2’3’-cGAMP-Y，cGAMP在鸟嘌呤部分有取代基修饰的衍生物(8-R3,R3＝氨基、卤素、甲氧基等)
(3)2’3’-cGAMP-XY，cGAMP在腺嘌呤和鸟嘌呤部分都有取代基修饰的衍生物(2-R1/8-R2,R1/R2＝氨基、卤素、甲氧基等；8-R3,R3＝氨基、卤素、甲氧基等)
(4)2’3’-cGAMP-XZ，cGAMP在腺嘌呤部分有取代基修饰，同时环化磷酸脂键部分的磷酸根有硫取代或硒取代的衍生物。
(5)2’3’-cGAMP-YZ，cGAMP在鸟嘌呤部分有取代基修饰，同时环化磷酸脂键部分的磷酸根有硫取代或硒取代的衍生物。
(6)2’3’-cGAMP-XYZ，cGAMP在腺嘌呤和鸟嘌呤部分都有取代基修饰，同时环化磷酸脂键部分的磷酸根有硫取代或硒取代的衍生物。
2’3’-cGAMP-XYZ衍生物的制备方法：
(1)三磷酸腺苷ATP和三磷酸鸟苷GTP的取代基衍生物，通过结合双联DNA后活化的环二核苷酸合成酶(cGAS)催化，制备2’3’-cGAM-XY衍生物(包括：2’3’-cGAMP-X，2’3’-cGAMP-Y，2’3’-cGAMP-XY)；
(2)α-磷酸硫取代(硒取代)的三磷酸腺苷ATP和三磷酸鸟苷GTP)的取代基衍生物，通过结合双联DNA后活化的环二核苷酸合成酶(cGAS)催化，制备α-磷酸硫取代(硒)取代-2’3’-cGAMP衍生物(包括：2’3’-cGAMP-XZ，2’3’-cGAMP-YZ，2’3’-cGAMP-XYZ)；
所述的2’3’-cGAMP衍生物在抗肿瘤中的用途是指医药或试剂等技术领域中，用于预防、治疗肿瘤及其直接相关疾病的产品，是包括药物、试剂等类型中的一种或多种。
本发明中，所述肿瘤包括但不限于结肠癌、肺癌、卵巢癌、黑色素瘤、胃癌等。
本发明中2’3’-cGAMP衍生物所制备的抗肿瘤药可以按常规药剂学制备成各种剂型，包括片剂、胶囊剂、颗粒剂、混悬剂、乳剂、溶液剂、糖浆剂或注射剂等。
本发明中2’3’-cGAMP衍生物抗肿瘤药可以采取口服或注射(包括静脉注射、静脉滴注、肌肉注射或皮下注射等中的一种或多种)等中的一种或多种给药途径进行肿瘤相关疾病的预防或治疗。
本发明提供的2’3’-cGAMP衍生物抗肿瘤药在肿瘤的药物治疗中具有良好的应用前景。
具体实施方式
下面通过实施例，具体说明本发明的内容。在本发明中，以下所述的实施例是为了更好地阐述本发明，并不是用来限制本发明的范围。
实施例1：环二核苷酸cGAMP衍生物组成和制备方法
(1)各种ATP和GTP的衍生物从美国Sigma公司购买。ATP和GTP的衍生物如下：
(a)ATP-X，ATP取代基修饰的衍生物(2-R1/8-R2,R1/R2＝氨基、卤素、甲氧基等)
(b)GTP-Y,GTP取代基修饰的衍生物(8-R3,R3＝氨基、卤素、甲氧基等)
(2)腺苷5’-α硫代(硒代)磷酸和鸟苷5’-α硫代(硒代)磷酸按文献方法制备。(HUANGZhen等，Science China,Chemistry,2012,55(1),80-89.,BoyleN.A.,etal,Nucleosides,Nucleotides and Nucleic Acids,2005,24,1651-1664.)所有化学试剂均购于Sigma公司。
(3)2’3’-cGAMP衍生物、硫(硒)代磷酸-2’3’-cGAMP衍生物的制备
参照2’3’-cGAMP的制备方法(PingweiLi，etal.,Immunity,2013,39(6),1019-1031.)，将ATP-X衍生物和GTP-Y衍生物替代ATP和GTP，在结合DNA结合后的活化条件下，由环化二核苷酸合成酶(cGAS)催化2’3’-cGAMP-XY衍生物(包括：2’3’-cGAMP-X，2’3’-cGAMP-Y，2’3’-cGAMP-XY)的合成，纯度在98％以上。
(4)硫(硒)代磷酸-2’3’-cGAMP-XYZ衍生物的制备，参照2’3’-cGAMP的制备方法，腺苷衍生物-5’-α硫代(硒代)磷酸和鸟苷衍生物-5’-α硫代(硒代)磷酸按文献方法制备。(HUANGZhen等，Science China,Chemistry,2012,55(1),80-89.,Boyle N.A.,etal,Nucleosides,Nucleotides and Nucleic Acids,2005,24,1651-1664.)5’-α硫代(硒代)磷酸腺苷衍生物ATP和5’-α硫代(硒代)磷酸鸟苷衍生物GTP，在结合DNA结合后的活化条件下，由环化二核苷酸合成酶(cGAS)催化硫(硒)代磷酸-2’3’-cGAMP-XYZ衍生物(包括：2’3’-cGAMP-XZ，2’3’-cGAMP-YZ，2’3’-cGAMP-XYZ)的合成，纯度在98％以上。
实施例2：环二核苷酸cGAMP衍生物用于抗肿瘤的动物实验
采用荷瘤鼠模型检测2’3’-cGAMP衍生物对动物皮下移植瘤生长的抑制作用及对动物的毒性作用。
用于抗肿瘤实验的2’3’-cGAMP衍生物选择如下五类：
(1)cGAMP-X1(2’3’-cGAMP中腺嘌呤2位氨基取代衍生物)
(2)cGAMP-Y1(2’3’-cGAMP中鸟嘌呤8位氨基取代衍生物)
(3)cGAMP-X1Y1(2’3’-cGAMP中腺嘌呤2位和鸟嘌呤8位氨基取代衍生物)
(4)cGAMP-X1Z1(cGAMP-X1中磷酸硫取代衍生物)
(5)cGAMP-X1Y1Z1(cGAMP-X1Y1中磷酸硫取代衍生物)
BALB/c普通小鼠、C57/BL6普通小鼠，雄性，体重16-18g，6-8周龄，SPF级，购于上海斯莱克实验动物有限责任公司[实验动物质量合格证号：SCXK(沪)2007-0005]。
饲养条件
所有小鼠均自由觅食和饮水，在室温(23±2)℃下饲养于中国人民解放军军医大学实验动物中心。饲料及水均经高压灭菌处理，全部实验饲养过程为SPF级。
剂量设置
静脉注射小鼠，设置1个剂量组：10mg/kg
试验对照
阴性对照：生理盐水溶液
阳性对照：cGAMP，剂量10mg/kg
给药方法
给药途径：尾静脉注射给药
给药体积：100微升/只
给药次数：每天1次，连续21天
每组动物数：10只
肿瘤细胞株
小鼠结直肠癌细胞株CT26，小鼠肺癌Lewis瘤株LL/2，人卵巢癌细胞株SK-OV-3，人黑色素瘤细胞株A375，人胃癌细胞株MNK-45均购自中国科学院细胞库。
试验主要步骤
1.肿瘤模型鼠的建立与干预
细胞培养，传代，在细胞对数期收集细胞，做成浓度为(1.0×107)每毫升的细胞悬液，小鼠右前肢腋下注射0.2ml细胞悬液(细胞数目为2.0×106个/只)，10天左右肿瘤长至直径约5mm，致瘤成功，随机均分为5组。分别为A：阴性对照组(静脉注射生理盐水组)；B：cGAMP组(静脉注射cGAMP)10mg/kg；C、D、E、F、G：2’3’-cGAMP衍生物组(静脉注射2’3’-cGAMP衍生物)10mg/kg。每天给药1次，连续给药21天。21天后，处死小鼠并称瘤体重量，抑瘤率＝[1-实验组平均瘤重(B、C、D、E、F、G组)/A组平均瘤重)]×100％。
分别制备皮下移植瘤模型：小鼠结直肠癌细胞株CT26，小鼠肺癌Lewis瘤株LL/2，人卵巢癌细胞株SK-OV-3，人黑色素瘤细胞株A375，人胃癌细胞株MNK-45，观察cGAMP衍生物抗肿瘤效果。
2.统计分析
数据用x±s表示，利用SPSS10.0软件进行处理，采用单因素方差分析(one-wayANOVA)检验比较各组瘤重差异的显著性，显著性水平a＝0.05。
结果
小鼠皮下接种肿瘤细胞后制备成功皮下移植瘤模型，2’3’-cGAMP-XYZ衍生物均可明显抑制肿瘤生长，给药21天后的瘤重均显著低于阴性对照组(P<0.05，P<0.01)，2’3’-cGAMP-XYZ优于cGAMP单独用药，表明2’3’-cGAMP-XYZ具有更优的抗肿瘤作用。具体结果表1-表5：
表1、cGAMP-XYZ对BalB/C小鼠结直肠癌细胞CT26皮下移植瘤的作用(n＝10，mean±SD)
注：*P<0.05vs阴性对照组；**P<0.01vs阴性对照组.
表2、cGAMP-XYZ对C57小鼠肺癌Lewis瘤株LL-2皮下移植瘤的作用(n＝10，mean±SD)
注：*P<0.05vs阴性对照组；**P<0.01vs阴性对照组.
表3、cGAMP-XYZ对人黑色素瘤细胞株A375鼠皮下移植瘤的作用(n＝10，mean±SD)
注：*P<0.05vs阴性对照组；**P<0.01vs阴性对照组.
表4、cGAMP-XYZ对人胃癌细胞株MNK-45鼠皮下移植瘤的作用(n＝10，mean±SD)
注：*P<0.05vs阴性对照组；**P<0.01vs阴性对照组.
表5、cGAMP-XYZ对人卵巢癌细胞株SK-OV-3鼠皮下移植瘤的作用(n＝10，mean±SD)
注：*P<0.05vs阴性对照组；**P<0.01vs阴性对照组.
实施例3cGAMP衍生物的急性毒性研究
实验材料
ICR小鼠20只(购于上海斯莱克实验动物有限责任公司[实验动物质量合格证号：SCXK(沪)2007-0005])，雌雄各半，体重18～22g，动物以颗粒饲料喂养，自由摄食和饮水。
cGAMP衍生物由实施例1制备，用生理盐水配制成浓度为200mg/mL的溶液。
实验方法
ICR小鼠按体重单次尾静脉注射2g/kg的cGAMP衍生物缓释药物，观察给药后小鼠14天内的毒性反应及死亡情况。结果发现，小鼠单次尾静脉注射给药后，小鼠活动正常。给药后14天内，小鼠未出现死亡，第15天，全部小鼠处死，解剖，肉眼检查各脏器，均未见明显病变。
实验结果
上述急性毒性实验结果表明，静脉注射给药最大耐受量MTD不低于2g/Kg，说明cGAMP衍生物药物的急性毒性低。
Claims (5)
1. 2’3’-cGAMP衍生物的分子结构组成：
由环二核苷酸2’3’-cGAMP进行修饰改造制备的2’3’-cGAMP衍生物如下：
2’3’-cGAMP-XYZ，cGAMP在腺嘌呤2位和鸟嘌呤8位都有氨基取代修饰，同时环化磷酸酯键部分的磷酸根有硫取代的衍生物。
2.运用权利要求1所述的2’3’-cGAMP衍生物制备的抗肿瘤药物，其特征在于：包含不同规格2’3’-cGAMP衍生物的单位制剂及药学上可接受的载体制备成的2’3’-cGAMP衍生物制剂，为片剂、胶囊剂、颗粒剂、混悬剂、乳剂、溶液剂、糖浆剂或注射剂中的一种或多种，采取口服或注射中的一种或多种给药途径进行肿瘤及其直接相关疾病的预防或治疗。
3.权利要求1所述的2’3’-cGAMP衍生物在制备用于预防、治疗肿瘤及其直接相关疾病的药物中的应用。
4.权利要求1所述的2’3’-cGAMP衍生物在制备与抗肿瘤化药联合用药中的应用。
5.权利要求1所述的2’3’-cGAMP衍生物在制备与抗肿瘤单克隆抗体联合用药中的应用。
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